tbuckley/cabot-search huggingface dataset:
Ophthalmologic Involvement in Adults with Histiocytic Disorders
Authors: Samantha A. Banks, M. Tariq Bhatti, Ronald S. Go, Jithma P. Abeykoon, Aldo A. Acosta-Medina, Antonious Z. Hazim, Gaurav Goyal, Jason R. Young, Matthew J. Koster, Robert Vassallo, Jay H. Ryu, Caroline J. Davidge-Pitts, Aishwarya Ravindran, Julio C. Sartori Valinotti, N. Nora Bennani, Mithun V. Shah, Karen L. Rech, James A. Garrity, W. Oliver Tobin
Journal: Ophthalmology (2022)
Molecular imaging to support cancer immunotherapy
Authors: Pim P van de Donk, Sjoukje F Oosting, Daan G Knapen, Anthonie J van der Wekken, Adrienne H Brouwers, Marjolijn N Lub-de Hooge, Derk-Jan A de Groot, Elisabeth GE de Vries
Journal: Journal for ImmunoTherapy of Cancer (2022)

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic.
Abstract Supplement 2018 ACR/ARHP Annual Meeting
Authors: Yves Allenbach, Yurdagul Uzunhan, Ségolène Toquet, Gaëlle Leroux, Laure Gallay, Aude Rigolet, Baptiste Hervier, Nicolas Champtiaux, Mathieu Vautier, Perrine Guillaume, Nicolas Limal, Alain Meyer, Christophe Deligny, Bernard Bonnotte, Hervé Devilliers, Sylvain Audia, Maxime Samson, Amélie Servettaz, Nathalie Costedoat, David Saadoun, Elisabeth Diot, Alice Berezne, Arsène Mékinian, Kuberaka Mariampillai, Hilario Nunes, Olivier Benveniste
Journal: Arthritis & Rheumatology (2018)

For a searchable version of these abstracts, please visit www.acrabstracts.org.
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

Tumor-associated macrophages (TAM) initiate and maintain a chronic inflammation in malignant tumors, which promotes tumor growth and metastasis. It becomes increasingly important to monitor the quantity and distribution of TAM in human tumors as new TAM-targeted cancer immunotherapies are developed. To solve this unmet clinical need, Aghighi and colleagues developed an MR imaging test for detection of TAM in sarcomas and lymphomas using the iron supplement ferumoxytol “off label” as an MRI-detectable TAM biomarker. In a first-in-human proof-of-concept clinical trial, the authors show that tumor ferumoxytol enhancement on MR images correlates with TAM quantities on histopathology.Bezrookove and colleagues examine the role of copy number elevations in the PHIP gene in melanoma progression using fluorescence in situ hybridization in three independent cohorts. The authors demonstrate an independent prognostic role for PHIP in primary melanoma, identify molecular subtypes of melanoma in which PHIP is enriched, and show that PHIP copy number is monotonically increased in the transition from primary to nodal to distant metastatic melanoma. Taken together with prior work showing that PHIP promotes melanoma metastasis in murine models, these results demonstrate a critical role for PHIP in melanoma progression, identifying PHIP as a promising target for therapy.To date, the epigenomic underpinnings of pituitary adenomas remains largely unexplored. Here, Salomon and colleagues leverage a multiomics study design to investigate the role of epigenetic alterations among PA subtypes. Genome-wide methylation analysis reveals that each pituitary adenoma subtype displays a disease-specific DNA methylation pattern. Furthermore, integrating DNA methylation and gene expression data revealed that hypomethylation of promoter regions drive increased expression of GH1 and SSTR5 genes in GH-secreting adenomas, and POMC gene in ACTH-secreting adenomas. The study suggests that epigenetic differences among pituitary adenoma subtypes play a crucial role and could be important in diagnosis and treatment decisions.Oncolytic viruses are demonstrating increasing promise as anticancer agents, with adenovirus (Ad) -based vectors proving popular. Efficacy could be enhanced through rational refinement of the capsid to maximize sequestration in cancerous cells. To achieve this, Uusi-Kerttula and colleagues redesigned the capsid to prevent uptake via all known native infectious routes and inserted a targeting peptide highly specific to the tumor-selective αvβ6 integrin. The resultant vector, Ad5NULL-A20, demonstrated exquisitely tumor-selective infection, minimal uptake in off-target organs, and significant efficacy in a model of ovarian cancer, thus providing a promising platform for future translational immuno-oncolytic applications.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2018)

PI3K Inhibitors and Insulin FeedbackAlthough mutations in PIK3CA, encoding the insulin-activated phosphoinositide-3-kinase (PI3K), occur commonly in cancer, variable clinical responses to PI3K inhibition suggest an inherent resistance mechanism.Importantly, PI3K inhibition disrupts glucose metabolism in several tissues.Blocking insulin signaling increases glycogen breakdown in the liver and inhibits glucose uptake in tissues, resulting in hyperglycemia.In patients with insulin resistance, hyperglycemia may require interruption of the therapy.Hopkins and colleagues showed in several mouse models that systemic glucose-insulin feedback caused by targeted inhibition of this pathway was sufficient to activate PI3K signaling, even in the presence of PI3K inhibitors.Moreover, feedback could be prevented by dietary or pharmacological approaches, which greatly enhanced the efficacy of these compounds.Expert Commentary: These findings may impact many PI3K inhibitors clinical trials and may provide a way to increase efficacy for patients.
Nanoparticulate drugs and vaccines: Breakthroughs and bottlenecks of repurposing in breast cancer
Authors: Popat Kumbhar, Kapil Kole, Varsha Khadake, Pradnya Marale, Arehalli Manjappa, Sameer Nadaf, Rajendra Jadhav, Ajit Patil, Sachin Kumar Singh, Kamal Dua, Niraj Kumar Jha, John Disouza, Vandana Patravale
Journal: Journal of Controlled Release (2022)
CD44 receptor targeted nanoparticles augment immunity against tuberculosis in mice
Authors: Vipul K. Singh, Eric Chau, Abhishek Mishra, Alexandro DeAnda, Venkatesh L. Hegde, Jagannadha K. Sastry, David Haviland, Chinnaswamy Jagannath, Biana Godin, Arshad Khan
Journal: Journal of Controlled Release (2022)
Engineered ionizable lipid siRNA conjugates enhance endosomal escape but induce toxicity in vivo
Authors: Annabelle Biscans, Socheata Ly, Nicholas McHugh, David A. Cooper, Anastasia Khvorova
Journal: Journal of Controlled Release (2022)

Lipid conjugation supports delivery of small interfering RNAs (siRNAs) to extrahepatic tissues, expanding the therapeutic potential of siRNAs beyond liver indications. However, siRNA silencing efficacy in extrahepatic tissues remains inferior to that routinely achieved in liver, partially due to the low rate of endosomal escape following siRNA internalization. Improving siRNA endosomal release into cytoplasm is crucial to improving efficacy of lipid-conjugated siRNAs. Given the ability of ionizable lipids to enhance endosomal escape in a context of lipid nanoparticles (LNP), here, we provide the first report on the effect of an ionizable lipid conjugate on siRNA endosomal escape, tissue distribution, efficacy, and toxicity in vivo. After developing a synthetic route to covalently attach the ionizable lipid, DLin-MC3-DMA, to siRNAs, we demonstrate that DLin-MC3-DMA enhances endosomal escape in cell culture without compromising siRNA efficacy. In mice, DLin-MC3-DMA conjugated siRNAs exhibit a similar overall tissue distribution profile to the similarly hydrophobic cholesterol-conjugated siRNA. However, only DLin-MC3-DMA conjugated siRNAs accumulated in vascular compartments, suggesting an effect of conjugate structure on intratissue distribution. Interestingly, we observed non-specific modulation of gene expression in tissues with high accumulation of DLin-MC3-DMA siRNAs (>20 pmol/mg of tissue) while limited non-specific gene modulation has been observed in tissues with lower siRNA accumulation. These findings suggest modulating the nature of the conjugate is a promising strategy to alter siRNA intratissue and intracellular trafficking. Fine-tuning the nature of the conjugate to optimize endosomal escape while minimizing toxicity will be critical for the progression of therapeutic siRNA applications beyond the liver.
Polysaccharide and conjugate vaccines to <i>Streptococcus pneumoniae</i> generate distinct humoral responses
Authors: Leela R. L. Davies, Deniz Cizmeci, Wenyue Guo, Corinne Luedemann, Ronika Alexander-Parrish, Lindsay Grant, Raul Isturiz, Christian Theilacker, Luis Jodar, Bradford D. Gessner, Galit Alter
Journal: Science Translational Medicine (2022)

Streptococcus pneumoniae is a major cause of community-acquired pneumonia, bacteremia, and meningitis in older adults worldwide. Two pneumococcal vaccines containing S. pneumoniae capsular polysaccharides are in current use: the polysaccharide vaccine PPSV23 and the glycoconjugate vaccine PCV13. In clinical trials, both vaccines elicit similar opsonophagocytic killing activity. In contrast to polysaccharide vaccines, conjugate vaccines have shown consistent efficacy against nasopharyngeal carriage and noninvasive pneumonia overall and for some prevalent individual serotypes. Given these different clinical profiles, it is crucial to understand the differential immunological responses induced by these two vaccines. Here, we used a high-throughput systems serology approach to profile the biophysical and functional features of serum antibodies induced by PCV13 and PPSV23 at 1 month and 1 year. In comparison with PPSV23, PCV13 induced higher titers across antibody isotypes; more durable antibody responses across immunoglobulin G (IgG), IgA, and IgM isotypes; and increased antigenic breadth. Although titers measured in opsonophagocytic activity (OPA) assays were similar between the two groups, confirming what was observed in clinical studies, serum samples from PCV13 vaccinees could induce additional non-OPA antibody-dependent functions, including monocyte phagocytosis and natural killer cell activation. In a multivariate modeling approach, distinct humoral profiles were demonstrated in each arm. Together, these results demonstrate that the glycoconjugate PCV13 vaccine induces an antigenically broader, more durable, polyfunctional antibody response. These findings may help explain the increased protection against S. pneumoniae colonization and noninvasive pneumonia and the longer duration of protection against invasive pneumococcal disease, mediated by PCV13.
Distinct immune-effector and metabolic profile of CD8<sup>+</sup>T cells in patients with autoimmune polyarthritis induced by therapy with immune checkpoint inhibitors
Authors: Karolina Benesova, Franziska Viktoria Kraus, Rui A Carvalho, Holger Lorenz, Christian H Hörth, Janine Günther, Karel D Klika, Jürgen Graf, Leonore Diekmann, Timo Schank, Petros Christopoulos, Jessica C Hassel, Hanns-Martin Lorenz, Margarida Souto-Carneiro
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Rheumatic immune-related adverse events (irAE) such as (poly)arthritis in patients undergoing immune checkpoint inhibitor (ICI) treatment pose a major clinical challenge. ICI therapy improves CD8 + T cell (CD8) function, but CD8 contributes to chronic inflammation in autoimmune arthritis (AA). Thus, we investigated whether immune functional and metabolic changes in CD8 explain the development of musculoskeletal irAE in ICI-treated patients. Methods Peripheral CD8 obtained from ICI-treated patients with and without arthritis irAEs and from AA patients with and without a history of malignancy were stimulated in media containing 13 C-labelled glucose with and without tofacitinib or infliximab. Changes in metabolism, immune-mediator release, expression of effector cell-surface molecules and inhibition of tumour cell growth were quantified. Results CD8 from patients with irAE showed significantly lower frequency and expression of cell-surface molecule characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and proinflammatory immune mediators compared with CD8 from ICI patients who did not develop irAE. This was accompanied by a higher glycolytic rate and ATP production. Gene-expression analysis of pre-ICI-treated CD8 revealed several differentially expressed transcripts in patients who later developed arthritis irAEs. In vitro tofacitinib or infliximab treatment did not significantly change the immune-metabolic profile nor the capacity to release cytolytic mediators that inhibit the growth of the human lung cancer cell line H838. Conclusions Our study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE has a distinct immune-effector and metabolic profile from those that remain irAE free. This specific irAE profile overlaps with the one observed in CD8 from AA patients and may prove useful for novel therapeutic strategies to manage ICI-induced irAEs.
Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression
Authors: María Juárez‐Fernández, Naroa Goikoetxea‐Usandizaga, David Porras, María Victoria García‐Mediavilla, Miren Bravo, Marina Serrano‐Maciá, Jorge Simón, Teresa C. Delgado, Sofía Lachiondo‐Ortega, Susana Martínez‐Flórez, Óscar Lorenzo, Mercedes Rincón, Marta Varela‐Rey, Leticia Abecia, Héctor Rodríguez, Juan Anguita, Esther Nistal, María Luz Martínez‐Chantar, Sonia Sánchez‐Campos
Journal: Hepatology (2022)

Background and Aims: Recent studies suggest that mitochondrial dysfunction promotes progression to NASH by aggravating the gut‐liver status. However, the underlying mechanism remains unclear. Herein, we hypothesized that enhanced mitochondrial activity might reshape a specific microbiota signature that, when transferred to germ‐free (GF) mice, could delay NASH progression. Approach and Results: Wild‐type and methylation‐controlled J protein knockout (MCJ‐KO) mice were fed for 6 weeks with either control or a choline‐deficient, L‐amino acid–defined, high‐fat diet (CDA‐HFD). One mouse of each group acted as a donor of cecal microbiota to GF mice, who also underwent the CDA‐HFD model for 3 weeks. Hepatic injury, intestinal barrier, gut microbiome, and the associated fecal metabolome were then studied. Following 6 weeks of CDA‐HFD, the absence of methylation‐controlled J protein, an inhibitor of mitochondrial complex I activity, reduced hepatic injury and improved gut‐liver axis in an aggressive NASH dietary model. This effect was transferred to GF mice through cecal microbiota transplantation. We suggest that the specific microbiota profile of MCJ‐KO, characterized by an increase in the fecal relative abundance of Dorea and Oscillospira genera and a reduction in AF12 , Allboaculum , and [ Ruminococcus ], exerted protective actions through enhancing short‐chain fatty acids, nicotinamide adenine dinucleotide (NAD + ) metabolism, and sirtuin activity, subsequently increasing fatty acid oxidation in GF mice. Importantly, we identified Dorea genus as one of the main modulators of this microbiota‐dependent protective phenotype. Conclusions: Overall, we provide evidence for the relevance of mitochondria–microbiota interplay during NASH and that targeting it could be a valuable therapeutic approach.
Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study
Authors: Seyi Soremekun, Liam G Heaney, Derek Skinner, Lakmini Bulathsinhala, Victoria Carter, Isha Chaudhry, Naeimeh Hosseini, Neva Eleangovan, Ruth Murray, Trung N Tran, Benjamin Emmanuel, Esther Garcia Gil, Andrew Menzies-Gow, Matthew Peters, Njira Lugogo, Rupert Jones, David B Price
Journal: Thorax (2022)

Progressive lung function (LF) decline in patients with asthma contributes to worse outcomes. Asthma exacerbations are thought to contribute to this decline; however, evidence is limited with mixed results.This historical cohort study of a broad asthma patient population in the Optimum Patient Care Research Database, examined asthma patients with 3+eligible post-18th birthday peak expiratory flow rate (PEF) records (primary analysis) or records of forced expiratory flow in 1 s (FEV1) (sensitivity analysis). Adjusted linear growth models tested the association between mean annual exacerbation rate (AER) and LF trajectory.We studied 1 09 182 patients with follow-up ranging from 5 to 50 years, of which 75 280 had data for all variables included in the adjusted analyses. For each additional exacerbation, an estimated additional -1.34 L/min PEF per year (95% CI -1.23 to -1.50) were lost. Patients with AERs >2/year and aged 18-24 years at baseline lost an additional -5.95 L/min PEF/year (95% CI -8.63 to -3.28) compared with those with AER 0. These differences in the rate of LF decline between AER groups became progressively smaller as age at baseline increased. The results using FEV1 were consistent with the above.To our knowledge, this study is the largest nationwide cohort of its kind and demonstrates that asthma exacerbations are associated with faster LF decline. This was more prominent in younger patients but was evident in older patients when it was related to lower starting LF, suggesting a persistent deteriorating phenotype that develops in adulthood over time. Earlier intervention with appropriate management in younger patients with asthma could be of value to prevent excessive LF decline.
Triple-negative breast cancer metastasis involves complex epithelial-mesenchymal transition dynamics and requires vimentin
Authors: Eloïse M. Grasset, Matthew Dunworth, Gaurav Sharma, Melanie Loth, Joseph Tandurella, Ashley Cimino-Mathews, Melissa Gentz, Sydney Bracht, Meagan Haynes, Elana J. Fertig, Andrew J. Ewald
Journal: Science Translational Medicine (2022)

Triple-negative breast cancer (TNBC) is an aggressive subtype associated with early metastatic recurrence and worse patient outcomes. TNBC tumors express molecular markers of the epithelial-mesenchymal transition (EMT), but its requirement during spontaneous TNBC metastasis in vivo remains incompletely understood. We demonstrated that spontaneous TNBC tumors from a genetically engineered mouse model (GEMM), multiple patient-derived xenografts, and archival patient samples exhibited large populations in vivo of hybrid E/M cells that lead invasion ex vivo while expressing both epithelial and mesenchymal characteristics. The mesenchymal marker vimentin promoted invasion and repressed metastatic outgrowth. We next tested the requirement for five EMT transcription factors and observed distinct patterns of utilization during invasion and colony formation. These differences suggested a sequential activation of multiple EMT molecular programs during the metastatic cascade. Consistent with this model, our longitudinal single-cell RNA analysis detected three different EMT-related molecular patterns. We observed cancer cells progressing from epithelial to hybrid E/M and strongly mesenchymal patterns during invasion and from epithelial to a hybrid E/M pattern during colony formation. We next investigated the relative epithelial versus mesenchymal state of cancer cells in both GEMM and patient metastases. In both contexts, we observed heterogeneity between and within metastases in the same individual. We observed a complex spectrum of epithelial, hybrid E/M, and mesenchymal cell states within metastases, suggesting that there are multiple successful molecular strategies for distant organ colonization. Together, our results demonstrate an important and complex role for EMT programs during TNBC metastasis.
Behçet’s disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity
Authors: Ann Cavers, Matthias Christian Kugler, Yesim Ozguler, Arshed Fahad Al-Obeidi, Gulen Hatemi, Beatrix M Ueberheide, Didar Ucar, Olivier Manches, Johannes Nowatzky
Journal: Annals of the Rheumatic Diseases (2022)

Objectives The endoplasmic reticulum aminopeptidase ( ERAP1 ) haplotype Hap10 encodes for a variant allotype of the endoplasmic reticulum (ER)-resident peptide-trimming aminopeptidase ERAP1 with low enzymatic activity. This haplotype recessively confers the highest risk for Behçet’s diseases (BD) currently known, but only in carriers of HLA-B*51 , the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact. Methods We genotyped and immune phenotyped a cohort of 26 untreated Turkish BD subjects and 22 healthy donors, generated CRISPR-Cas9 ERAP1 KOs from HLA-B*51 + LCL, analysed the HLA class I-bound peptidome for peptide length differences and assessed immunogenicity of genome-edited cells in CD8 T cell co-culture systems. Results Allele frequencies of ERAP1-Hap10 were similar to previous studies. There were frequency shifts between antigen-experienced and naïve CD8 T cell populations of carriers and non-carriers of ERAP1-Hap10 in an HLA-B*51 background. ERAP1 KO cells showed peptidomes with longer peptides above 9mer and significant differences in their ability to stimulate alloreactive CD8 T cells compared with wild-type control cells. Conclusions We demonstrate that hypoactive ERAP1 changes immunogenicity to CD8 T cells, mediated by an HLA class I peptidome with undertrimmed peptides. Naïve/effector CD8 T cell shifts in affected carriers provide evidence of the biological relevance of ERAP1-Hap10/HLA-B*51 at the cellular level and point to an HLA-B51-restricted process. Our findings suggest that variant ERAP1-Hap10 partakes in BD pathogenesis by generating HLA-B51-restricted peptides, causing a change in immunodominance of the ensuing CD8 T cell response.